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INTRODUCTION — Group A streptococcal (GAS) tonsillopharyngitis presents with abrupt onset of sore throat, tonsillar exudate, tender cervical adenopathy, and fever, followed by spontaneous resolution within two to five days. Patients with sore throat lasting longer than one week usually do not have GAS tonsillopharyngitis.

Considerations of treatment include ease of antibiotic administration and limited expense with as few adverse effects as possible [2-4].

Reducing clinical symptoms — Antibiotic therapy is most beneficial for hastening resolution of symptoms if instituted within the first two days of illness [5-9]. Antibiotic therapy is also beneficial for reducing suppurative complications such as peritonsillar abscess, cervical lymphadenitis, and mastoiditis. Additional issues related to antibiotic therapy for reducing clinical symptoms are discussed further below. (See 'Timing of therapy' below.)

Reducing nonsuppurative complications — Antibiotic therapy is primarily helpful for reducing the incidence of acute rheumatic fever as a nonsuppurative complication of GAS pharyngitis. The role of antibiotic therapy in decreasing the nonsuppurative complications of glomerulonephritis and pediatric autoimmune neuropsychiatric disorder associated with group A streptococci (PANDAS) syndrome is not clear [10].

The efficacy of penicillin for primary prevention of ARF was established in the early 1950s when military recruits with GAS tonsillopharyngitis received injectable penicillin G mixed in peanut oil or sesame oil with 2 percent aluminum monostearate [13,14]. GAS eradication and ARF primary prevention were optimized with injection schedules that provided at least 9 to 11 days of penicillin.

Subsequently, evaluation of GAS tonsillopharyngitis therapies has been based upon GAS eradication from the upper respiratory tract; it is assumed that such eradication is an adequate surrogate marker for efficacy in primary prevention of rheumatic fever. Antibiotic therapy can be helpful for prevention of rheumatic fever if initiated up to nine days following onset of symptoms [13].

Reducing transmission — The rate of GAS transmission from an infectious case to close contacts (such as a family or school setting) is approximately 35 percent. Antibiotic treatment does have a role for preventing transmission of GAS; after 24 hours of treatment with penicillin, subsequent cultures are negative in about 80 percent of cases [15]. Data on the duration of contagion for alternative antibiotics are not available. In untreated patients, GAS is eliminated from the upper respiratory tract by host immune factors in 50 percent of cases at one month following acute infection [16].

Antimicrobial therapy may also be administered to mitigate the clinical course of pharyngitis due to group C and group G streptococci. The approach to antibiotic selection is as outlined in the following sections. However, treatment need not continue for 10 days since acute rheumatic fever is not a complication of infection due to these organisms; five days of treatment is sufficient [2,17,18]. (See "Group C and group G streptococcal infection".)

In general, antimicrobial therapy is of no proven benefit for treatment of pharyngitis due to bacteria other than Streptococcus (with the exception of relatively rare infections caused by other bacterial pathogens such as Corynebacterium diphtheriae and Neisseria gonorrhoeae). Such therapy unnecessarily exposes patients to the expense and potential hazards of antimicrobial drugs and contributes to the emergence of antibiotic resistant bacteria.

Timing of therapy — If clinical and/or epidemiologic factors point to a high index of suspicion for GAS pharyngitis while laboratory results are pending, it is appropriate to initiate empiric antimicrobial therapy. However, if laboratory testing does not confirm the diagnosis of GAS pharyngitis, antimicrobial therapy should be discontinued.

In the natural history of GAS pharyngitis, the incubation period is two to four days. Fever and constitutional symptoms usually resolve within three to four days, even in the absence of antimicrobial therapy [16]. Clinical improvement has been observed up to 48 hours sooner in patients receiving penicillin versus placebo within the first two days of illness [5-9].

There is some concern that early therapy may suppress host antibody response and thereby increase risk for recurrent pharyngitis. In a study of 142 children with presumed GAS pharyngitis, those treated with penicillin at the initial office visit had a higher incidence of recurrent infection than those for whom treatment was delayed at least 48 hours (recurrent infection occurred eight times more frequently) [6].

Nonetheless, delaying treatment is not warranted in most cases of GAS tonsillopharyngitis. It may be a useful strategy for patients who have frequent, recurrent, mild to moderate infections to allow development of immunity to the infecting strain without increasing the risk of acute rheumatic fever. Antibiotic therapy delayed for up to nine days following onset of symptoms is still helpful for prevention of rheumatic fever (although may be less effective for prevention of suppurative complications) [13]. However, this approach should not be considered if the patient is severely ill or if highly virulent or rheumatogenic strains are actively circulating within a community. Patients are considered no longer contagious after 24 hours of antibiotic therapy [15].

Antibiotics for group A Streptococcus — Antibiotic options for treatment of GAS pharyngitis include penicillin (and other related agents including ampicillin and amoxicillin), cephalosporins, macrolides, and clindamycin [19]. Sulfonamides, fluoroquinolones, and tetracyclines should NOT be used for treatment of GAS pharyngitis because of high rates of resistance to these agents and their frequent failure to eradicate even susceptible organisms from the pharynx.

Intramuscular penicillin is the only therapy that has been shown to prevent initial attacks of rheumatic fever in controlled studies [14,20]. These studies were performed with penicillin G procaine in oil containing aluminum monostearate; this preparation has since been supplanted by penicillin G benzathine. There are data suggesting that penicillin G benzathine is effective for primary prevention of rheumatic fever, although they are not definitive [21]. Other antimicrobials have been shown to effectively eradicate GAS from the upper respiratory tract, and it is assumed that such eradication is a surrogate for efficacy in primary prevention of rheumatic fever.

Resistance — Antimicrobial resistance has not been a significant issue in the treatment of GAS. No clinical isolate of GAS has demonstrated penicillin resistance, likely due to the organism's lack of altered penicillin-binding proteins and/or inefficient gene transfer mechanisms for resistance [22,23]. However, streptococcal strains tolerant to penicillin (eg, strains inhibited but not killed by penicillin in vitro, with ratio of minimum bactericidal concentration to minimum inhibitory concentration [MIC] of ≥32) have been described [24-27]. The clinical significance of such strains is not clear; they have been isolated in the setting of outbreaks in which penicillin treatment failure was observed, but there was no difference in failure rates among tolerant and susceptible strains. (See "Antibiotic failure in the treatment of streptococcal tonsillopharyngitis".)

There have been reports of relatively high levels of resistance to macrolide antibiotics in some regions of the United States and Asia; given the increasing use of macrolides for treatment of upper and lower respiratory tract infections, clinicians should be cognizant of local patterns of antimicrobial resistance [28-37].

Selection — Oral penicillin V is the agent of choice for treatment of GAS pharyngitis given its proven efficacy, safety, narrow spectrum, and low cost [2,38-42]. The appropriate duration is 10 days of therapy; dosing is outlined in the Table (table 1). This approach is extrapolated from studies performed in the 1950s demonstrating that treatment of streptococcal pharyngitis with intramuscular penicillin prevents acute rheumatic fever [14,20]. (See "Treatment and prevention of acute rheumatic fever".)

Amoxicillin is often used in place of oral penicillin in children, since the taste of the amoxicillin suspension is more palatable than that of penicillin. Some data suggest that oral amoxicillin may be marginally superior to penicillin, most likely due to better gastrointestinal (GI) absorption [43,44]. In addition, amoxicillin has activity against one-third of the common pathogens that cause otitis media (which presents concurrently with GAS tonsillopharyngitis in up to 15 percent of children, particularly those under four years of age). Dosing is outlined in the Table (table 1). (See "Acute otitis media in children: Treatment", section on 'Initial antimicrobial therapy'.)

Intramuscular penicillin G benzathine (single dose) may be administered to patients who cannot complete a 10-day course of oral therapy or to patients at enhanced risk for rheumatic fever (eg, those with history of previous rheumatic heart disease and/or living in crowded conditions). Injections of benzathine penicillin provide bactericidal levels against GAS for 21 to 28 days. The addition of procaine penicillin alleviates some of the discomfort associated with benzathine injections and may favorably influence the initial clinical response. The preferred product in children is the combination of 900,000 units of benzathine penicillin G plus 300,000 units of procaine penicillin (Bicillin C-R 900/300). (See Penicillin G benzathine-penicillin G procaine: Drug information). Dosing is outlined in the Table (table 1).

Cephalosporins are acceptable alternatives in patients with recurrent GAS infection but are not recommended as first-line therapy in national guidelines [45-52]. Cephalosporins have demonstrated better microbiologic and clinical cure rates than penicillin; these differences appear to be greater among children than adults, and some favor use of first-generation cephalosporins as first-line therapy in this group [53-55]. However, second- and third-generation cephalosporins may facilitate development of antibiotic resistance and are not favored as first-line therapy [46,47]. (See 'Recurrent infection' below.)

Antibiotic therapy directed against beta-lactamase-producing upper respiratory tract flora (such as amoxicillin-clavulanate) remains controversial and is not indicated in patients with acute pharyngitis, although it would be effective [2,56,57].

For patients with beta-lactam hypersensitivity, cephalosporins (cefuroxime, cefpodoxime, cefdinir, and ceftriaxone) may be used [38,44-50], in the absence of history of life-threatening allergic reaction to penicillin; cross reactivity with penicillin is not likely for later-generation cephalosporins than first-generation cephalosporins [45,58-60]. Macrolides (clarithromycin, azithromycin, or erythromycin) are an acceptable alternative for penicillin-allergic patients, depending on local resistance patterns [28,31-36]. For the rare patient with an erythromycin-resistant strain of GAS who is unable to tolerate beta-lactam agents, clindamycin is an appropriate choice [61].

Duration — In general, the conventional duration of oral antibiotic therapy to achieve maximal pharyngeal GAS eradication rates is 10 days, even though patients usually improve clinically within the first few days of treatment [62,63]. If penicillin is discontinued after three days of therapy, the probability of relapse is higher than if penicillin is discontinued after seven days of treatment (50 versus 34 percent, respectively) [14,16,20].

Five days of therapy with cefpodoxime, cefdinir, or azithromycin is an acceptable alternative approach, with rates of bacteriologic and clinical cure of streptococcal pharyngitis comparable with that of the conventional 10-day course of penicillin [33-36,41,64-76]. Three injections of ceftriaxone on sequential days (or every other day) are needed for optimal eradication.

Attempts to treat GAS pharyngitis with a single daily dose of penicillin have been unsuccessful. Although some data suggest that once-daily amoxicillin may be sufficient for treatment of GAS pharyngitis, others have shown that this approach is not adequate for effective eradication; further investigation is needed [77-80]. Among the alternative agents, azithromycin and some cephalosporins (including cefixime, cefpodoxime, cefadroxil, and cefdinir) are effective for eradication of pharyngeal streptococci with once-daily dosing [69,81-84].

The approach to treatment of infection due to Fusobacterium necrophorum is uncertain; further study is needed to better define the role of F. necrophorum in the epidemiology of pharyngitis and the associated risk between F. necrophorum pharyngitis and Lemierre’s syndrome. Some favor empiric treatment in the setting of negative diagnostic test results but at least three Centor criteria (fever, tonsillar exudate, swollen tender cervical adenopathy, or lack of cough) among patients 15 to 30 years of age, although it is uncertain whether this approach is effective for prevention of Lemierre’s syndrome [85-87]. In general, we favor treatment for pharyngitis only in the setting of a positive diagnostic test [41]. Antibiotic therapy for pharyngitis attributed to F. necrophorum should consist of a penicillin or cephalosporin; azithromycin lacks activity. (See "Suppurative (septic) thrombophlebitis", section on 'Jugular vein' and "Evaluation of acute pharyngitis in adults", section on 'Evaluation'.)

The antibiotics of choice for treatment of infection due to Arcanobacterium haemolyticum are erythromycin or azithromycin; data are limited to case reports and in vitro studies [88,89]. In vitro studies show most strains to be susceptible to beta-lactam agents, although treatment failure may occur because of poor penetration into the intracellular space [89]. Clindamycin, doxycycline, ciprofloxacin, and vancomycin are also effective agents.

Follow-up — Patients with GAS pharyngitis should have improvement in clinical symptoms within three to four days of initiating antibiotic therapy. Failure to observe a clinical response to antibiotics should prompt diagnostic reconsideration or the possibility of a suppurative complication. If acute streptococcal pharyngitis was diagnosed by rapid testing, the result may represent a false-positive finding; if the diagnosis was made by culture, the patient may be a pharyngeal carrier whose symptoms are likely attributable to an alternate process. (See 'Carriers' below.)

In general, test of cure is not necessary for asymptomatic patients or their close contacts following completion of a course of antimicrobial therapy. The majority of patients with GAS remaining in their upper respiratory tracts after completing a course of antimicrobial therapy are Streptococcus carriers [90,91].

However, follow-up test of cure is appropriate testing for asymptomatic index patients and their asymptomatic household contacts in the following circumstances:

Asymptomatic patients and asymptomatic household contacts in the above circumstances with positive laboratory results should receive a standard course of antimicrobial therapy with one of the agents outlined above [92]. Repeat treatment should be administered with an agent with greater beta-lactamase stability than the previous agent [56]. If a penicillin was used for initial therapy, repeat treatment with amoxicillin-clavulanate or a first-generation cephalosporin may be used; if initial treatment was with a first-generation cephalosporin, a second- or third-generation cephalosporin may be used. (See "Evaluation of acute pharyngitis in adults" and 'Antibiotics for group A Streptococcus' above.)

Recurrent infection — In the setting of recurrent acute pharyngitis with positive repeat diagnostic testing, there are several possible explanations [90,92,93]:

●Persistence of Streptococcus carriage in the setting of viral infection

In the setting of a second episode of acute pharyngitis with positive repeat diagnostic testing, a repeat course of treatment is appropriate (table 1). Repeat treatment should be administered with an agent with greater beta-lactamase stability than the previous agent [56].

It is not necessary to perform follow-up testing after the second course of therapy unless the patient remains or becomes symptomatic or unless special circumstances as outlined above are present. (See 'Antibiotics for group A Streptococcus' above and 'Follow-up' above.)

In the setting of multiple recurrent episodes, it may be difficult to distinguish true GAS pharyngitis from viral pharyngitis in the setting of streptococcal carriage. It is likely that most of these patients are carriers experiencing nonstreptococcal infections. This may be discernible by evaluating for the presence of GAS during asymptomatic intervals and/or by typing streptococcal isolates obtained during distinct episodes (with the expertise of a specialized laboratory). In these circumstances, treatment with clindamycin or amoxicillin-clavulanate may be beneficial since these agents have demonstrated high eradication rates for pharyngeal streptococci carriage (table 1) [56,61,94]. (See 'Carriers' below.)

Carriers — In general, group A Streptococcus (GAS) resides in the oropharynx of Streptococcus carriers in the absence of host immunologic response to the organism [97]. In temperate climates during the winter and spring, up to 20 percent of asymptomatic school-aged children may be carriers. About 25 percent of asymptomatic individuals in the households of index patients harbor GAS in their upper respiratory tracts [92]. Streptococcal carriage may persist for many months. (See "Antibiotic failure in the treatment of streptococcal tonsillopharyngitis", section on 'Streptococcal carriage'.)

Carriers may demonstrate evidence of GAS in the upper respiratory tract during an episode of viral pharyngitis, suggesting acute streptococcal pharyngitis. In these circumstances, clinically distinguishing viral from streptococcal pharyngitis can be difficult. Useful clues may include patient age, season, local epidemiology, and the nature of presenting signs and symptoms. In addition, pharyngeal strep carriers tend to have low antistreptolysin O (ASO) titers; they may be just above detectable. (See "Evaluation of acute pharyngitis in adults".)

Streptococcus carriers are unlikely to spread the organism to close contacts and are at very low risk for developing suppurative complications or acute rheumatic fever [97]. Moreover, eradication of GAS from the upper respiratory tract of carriers is much more difficult than eradication of GAS from patients with acute infection [50,90,98]. In general, except for the circumstances described above, Streptococcus carriers do not require antimicrobial therapy. (See 'Follow-up' above.)

Foodborne illness — Streptococcal contamination of food has been implicated in foodborne outbreaks of pharyngitis [99-103], and foodborne transmission of GAS pharyngitis by asymptomatic food service workers with nasopharyngeal carriage has been reported [102,104,105]. Factors that can reduce foodborne transmission of GAS pharyngitis include thorough cooking, complete reheating, and use of gloves while handling food [99,106].

Vaccination — There is no vaccine against GAS available for clinical use, although development of this preventive measure is under investigation [107,108]. An important area of uncertainty is whether vaccine-induced antibodies may cross-react with host tissue to produce nonsuppurative sequelae in the absence of clinical infection.

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•Reducing transmission to close contacts by reducing infectivity (see 'Goals of therapy' above)

●We recommend initiating treatment with antimicrobial therapy for patients with symptomatic pharyngitis if the presence of group A streptococci in the pharynx is confirmed by culture or rapid antigen detection testing (RADT) (Grade 1A). (See 'Treatment' above.)

●Oral penicillin V is the agent of choice for treatment of GAS pharyngitis in many clinical settings given its proven efficacy, safety, narrow spectrum, and low cost. Amoxicillin is often used in place of oral penicillin in children, since the taste of the amoxicillin suspension is more palatable than that of penicillin (table 1). First-generation cephalosporins are an acceptable alternative to penicillin and amoxicillin, especially in the setting of treatment failure or beta-lactam hypersensitivity. (See 'Selection' above.)

●Although most patients improve clinically within the first few days of treatment, the conventional duration of oral antibiotic therapy is 10 days to achieve maximal pharyngeal GAS eradication rates. Intramuscular penicillin G benzathine may be administered to patients who cannot complete a 10-day course of oral therapy. (See 'Duration' above.)

●In general, test of cure is not necessary for asymptomatic patients or their close contacts following completion of a course of antimicrobial therapy, except in unique circumstances. (See 'Follow-up' above.)

●We suggest a repeat course of treatment for patients with a repeat episode of acute pharyngitis and positive repeat diagnostic testing (Grade 2C). Patients warranting a repeat course of treatment may receive an agent with greater beta-lactamase stability than the previous agent. (See 'Recurrent infection' above.)

●Patients who are long-term streptococcal carriers may develop multiple episodes of pharyngitis due to viral infection. In such cases, repeatedly positive cultures or rapid antigen tests for GAS may be misleading, and further treatment for streptococcal pharyngitis may not be warranted. Carriers are unlikely to spread the organism to close contacts and are at very low risk for developing suppurative complications or acute rheumatic fever. Moreover, eradication of GAS from the upper respiratory tract of carriers can be difficult and is not necessary. (See 'Carriers' above.)